Osteogenesis imperfecta

As we have previously mentioned, OI is a very heterogeneous disease with very diverse clinical manifestations and a wide spectrum of severity. In recent years, there has been an advance in describing the multiple genes involved in osteogenesis imperfecta, which in turn has brought about important changes in its classification.

If we return to our initial classification, we spoke of OI congenita in those individuals born with fractures, and OI tarda when the fractures are produced after birth. OI tarda may be subdivided into OI gravis—fractures occur in the first year of life—and OI levis—fractures occur from the second year onward.

In 1979, Sillence and colleagues observed the clinical characteristics and the pattern of inheritance of a large series of Australian patients with OI, and classified them into four types: 

• TYPE I. This is the mildest form, with no deformity and with blue sclerae; autosomal dominant inheritance.
• TYPE II. This is a fatal perinatal form with multiple fractures and severe deformities leading to death in the perinatal period.
• TYPE III. This form is severe and progressively deforming, with scoliosis and white sclerae.
• TYPE IV. This is the most heterogeneous group, with moderate deformities, variably colored sclerae, and dentinogenesis imperfecta.

The Sillence classification has been widely used for many years. Nevertheless, in the year 2000, Glorieux and colleagues observed that some patients that had been classified as Sillence type IV showed specific clinical characteristics, such as the presence of hypertrophic osseous calluses and calcification of the interosseous membrane between the radius and the ulna, producing limited rotational mobility of the forearm. They proposed widening the classification system to include these patients in a new group, OI type V. Years later it was discovered that these patients had a mutation in the IFITM5 gene.

Some years later, Glorieux's group identified a subgroup of patients with moderate-to-severe OI who, on bone biopsy, showed specific characteristics that distinguished them from other patients. Observing their bone tissue under the microscope, they saw a thick, under-mineralized osteoid. They proposed then to classify these patients as OI type VI. Years later, it was discovered that these patients had a mutation in the SERPINF1 gene.

With the recognition in recent years of newly discovered genes implicated in OI, researchers have added new groups to the classification system (Table 1). Nevertheless, this classification system is not currently used. It is more common to classify patients in terms of the level of clinical effects of OI (mild, moderate, severe, fatal) and then add the genetic mutation.

AD: Autosomal dominant, AR: Autosomal recessive

The forms related to mutations in the genes PLOD2, PLS3, SEC24D, P4HB and NBAS, which have been included in this chapter because of their relation to OI, have not been classified as numeric subtypes of OI.